7-114426635-T-A

Position:

• chr7-114426635-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014491.4(FOXP2):​c.124T>A​(p.Ser42Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S42C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXP2 NM_014491.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

Genes affected

FOXP2 (HGNC:13875): (forkhead box P2) This gene encodes a member of the forkhead/winged-helix (FOX) family of transcription factors. It is expressed in fetal and adult brain as well as in several other organs such as the lung and gut. The protein product contains a FOX DNA-binding domain and a large polyglutamine tract and is an evolutionarily conserved transcription factor, which may bind directly to approximately 300 to 400 gene promoters in the human genome to regulate the expression of a variety of genes. This gene is required for proper development of speech and language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways and cascades that may ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorder with orofacial dyspraxia. Multiple alternative transcripts encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FOXP2. . Gene score misZ 1.8963 (greater than the threshold 3.09). Trascript score misZ 3.108 (greater than threshold 3.09). GenCC has associacion of gene with childhood apraxia of speech, specific language disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13244072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.124T>A	p.Ser42Thr	missense_variant	2/17	ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.124T>A	p.Ser42Thr	missense_variant	2/17	1	NM_014491.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459716 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.124T>A (p.S42T) alteration is located in exon 2 (coding exon 1) of the FOXP2 gene. This alteration results from a T to A substitution at nucleotide position 124, causing the serine (S) at amino acid position 42 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.079	T;T;.;T;.;.;.;T;T;T;.;T;.;.;T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T;T;T;.;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.069	D
MutationAssessor	Benign	0.69	.;.;.;N;.;N;N;N;.;.;N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.69	.;.;.;N;N;N;N;N;N;N;N;.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.17	.;.;.;T;T;T;T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.94, 0.49, 0.0	.;.;.;P;.;.;P;P;.;.;.;.;B;.;B
Vest4		0.29
MutPred		0.090		Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);.;
MVP		0.85
MPC		0.39
ClinPred		0.62	D
GERP RS		2.4
Varity_R		0.15
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-114066690;